ErbB/HER receptors form a subfamily of receptor tyrosine kinases that includes EGFR (also known as ErbB1 or HER1), HER2 (c-Neu, ErbB2), HER3 (ErbB3), and HER4 (ErbB4). ErbB receptors are selectively activated by a number of EGF-like growth factors leading to cellular responses, such as cell proliferation, differentiation, migration, or survival. ErbB receptors consist of a glycosylated extracellular domain, a single transmembrane domain, and an intracellular domain including a tyrosine kinase enzyme. Ligand binding to the receptor extracellular domain triggers receptor dimerization, subsequent activation of the kinase domain, receptor autophosphorylation, and multiple downstream signaling cascades (1).
EGFR and HER2 are well-established oncogenes and cancer drug targets. They are implicated in the pathogenesis of various epithelial and neural malignancies, and their overactivity is associated with poor patient outcome (2-4). Targeted therapeutics including both monoclonal antibodies and small molecular weight kinase inhibitors blocking the functions of these receptors have shown therapeutic effect on patient survival in clinical trials. Cetuximab (ERBITUX™, Imclone, Inc.) is a chimeric monoclonal antibody that blocks ligand binding to EGFR, leading to a decrease in receptor dimerization, autophosphorylation and activation of signaling pathways (5). Cetuximab is currently approved for clinical use in late-stage chemorefractory colorectal cancer and locally or regionally advanced squamous cell carcinoma of the head and neck. Trastuzumab (HERCEPTIN™, Genentech, Inc.) is a humanized monoclonal antibody against the extracellular domain of HER2 currently used for the treatment of ErbB2-overexpressing breast cancers in both adjuvant setting and for advanced disease (6-9).
HER4 receptor antagonists have been shown to be useful in controlling excessive migration and/or proliferation or smooth muscle cells and, in particular, for the treatment of stenosis. See U.S. Pat. No. 7,332,579.
The significance of HER4 in cancer is poorly understood. Some observations indicate that HER4 receptor is down-regulated in various cancers, or that its expression is associated with favorable prognostic markers, such as estrogen receptor expression (10, 11). On the other hand, HER4 has been reported to have high expression levels in several cancers such as thyroid (12), ovarian (13), and breast cancer (14), as well as medulloblastoma (15), and ependymoma (16). Furthermore, the significance of HER4 expression levels for clinical outcome is conflicting (17). One of the plausible explanations for these contradictory data is that four structurally and functionally different isoforms are generated from a single HER4 gene by alternative splicing (18, 19). These isoforms have different tissue distribution profiles and differ in their ability to promote tumorigenesis in breast cancer cell lines (26).
Accordingly, it is desirable to provide a therapeutic that is directed to specific isoforms of the HER4 receptor to more precisely treat HER4 mediated disorders.